Peptides and Small-molecules Targeting Signaling Proteins and Protein-Protein Interfaces

靶向信号蛋白和蛋白质-蛋白质界面的肽和小分子

• 批准号: 10654749
• 负责人: Harish Vashisth
• 金额: $ 36.49万
• 依托单位: UNIVERSITY OF NEW HAMPSHIRE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654749
• 关键词: Acceleration; Address; Agonist; Allosteric Site; Binding; Cell Surface Receptors; Cone; Data; Diabetes Mellitus; Extracellular Domain; Family; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits; GTP-Binding Proteins; Growth; Growth Factor; Hormones; Insulin; Malignant Neoplasms; Mediator; Metabolic; Modeling; Molecular; Pathway interactions; Peptides; Protein Family; Proteins; RGS Proteins; Research; Signal Transduction; Signaling Protein; Snail Venoms; Therapeutic Intervention; Viral; Vision Disorders; Visual; antagonist; computer studies; design; genetic regulatory protein; insulin-like peptide; mimetics; nervous system disorder; novel; novel therapeutic intervention; peptide analog; peptidomimetics; protein protein interaction; receptor; small molecule; small molecule inhibitor

Cell-surface receptors and intracellular regulatory proteins are preeminent mediators of cellular signaling as these proteins are involved in a host of interactions and pathways. Therefore, various stages of their signaling cycles provide unique opportunities for therapeutic intervention. This project presents computational studies integrated with experimental data to resolve the mechanisms of recognition of novel peptide mimetics and analogues targeting extracellular domains of receptor proteins of the insulin family and small-molecules targeting intracellular protein-protein interactions in regulatory proteins of the G-protein coupled receptor (GPCR) family. The proposed studies are timely in that several recent structural studies have revealed the binding modes of the native hormone insulin and homologous growth factor peptides and we have developed dynamics-based computational approaches that have opened the avenues for designing novel peptide-based agonists and antagonists. Toward this direction are our proposed studies of three classes of peptides: (1) synthetic insulin mimetics, (2) viral-insulin-like peptides (VILPs), and insulin-like peptides from cone snail venom. Our second research direction aims to develop small-molecule inhibitors targeting a key intracellular protein-protein interaction between regulators of G-protein signaling (RGS) proteins and the alpha-subunits of G-proteins. As opposed to the conventional approach of directly targeting the protein-protein interface, we propose to target allosteric sites on RGS proteins to inhibit the protein-protein interaction. Through preliminary studies on a model protein, we have shown that allosteric control and targeting is feasible and through this project we propose to broaden the scope of these promising studies to new protein targets involved in cancer and visual signaling. Overall, we anticipate that the mechanistic paradigms emerging from these studies will have broader applicability to other protein families and will facilitate the design of novel therapeutic strategies.

细胞表面受体和细胞内调节蛋白是细胞调控的重要介质

项目成果

Mechanism of Ligand Discrimination by the NMT1 Riboswitch

• DOI: 10.1021/acs.jcim.3c00835
• 发表时间: 2023-07
• 期刊: Journal of chemical information and modeling
• 影响因子: 5.6
• 作者: Amit Kumar;Harish Vashisth

Structural and computational studies of HIV-1 RNA.

• DOI: 10.1080/15476286.2023.2289709
• 发表时间: 2024-01
• 期刊: RNA BIOLOGY
• 影响因子: 4.1
• 作者: Levintov, Lev;Vashisth, Harish
• 通讯作者: Vashisth, Harish

Quantitative Assessment of Energetic Contributions of Residues in a SARS-CoV-2 Viral Enzyme/Nanobody Interface

• DOI: 10.1021/acs.jcim.3c01933
• 发表时间: 2024-03-09
• 期刊: JOURNAL OF CHEMICAL INFORMATION AND MODELING
• 影响因子: 5.6
• 作者: Kumar，Amit;Vashisth，Harish
• 通讯作者: Vashisth，Harish

Progress in Simulation Studies of Insulin Structure and Function.

• DOI: 10.3389/fendo.2022.908724
• 发表时间: 2022
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2
• 作者: Gorai B;Vashisth H
• 通讯作者: Vashisth H

Adenine Methylation Enhances the Conformational Flexibility of an RNA Hairpin Tetraloop

• DOI: 10.1021/acs.jpcb.4c00522
• 发表时间: 2024-03-27
• 期刊: JOURNAL OF PHYSICAL CHEMISTRY B
• 影响因子: 3.3
• 作者: Levintov，Lev;Vashisth，Harish
• 通讯作者: Vashisth，Harish